CD8 NK/T Cells and the Phylogeny of Cellular Immunity

CD8细胞毒性T淋巴细胞(CTL)识别和杀伤在主要组织相容性复合体(MHC)I类分子背景下表达抗原肽的靶标。因此，CTL在产生针对病毒和肿瘤的获得性免疫中起着至关重要的作用。自然杀伤(NK)细胞通过检测和杀死病毒感染或肿瘤细胞，下调其表面MHC-I类分子，从而逃避适应性免疫系统的监视，在先天性免疫中发挥积极作用。越来越多的证据表明，一些免疫反应是由表达NK相关分子(CD8/NK T细胞)的CTL介导的。NK相关分子的复杂性和异质性以及它们在不同效应分子(如CTL)中的表达，其生物学和生理学意义尚不清楚。由于某些热休克蛋白(如gp96或HSP70)既能诱导CD8T细胞对其伴侣抗原肽的适应性反应，又能诱导先天性免疫反应，这一点在包括蛙类在内的几个物种中都得到了很好的证实，因此首次探索这种假定的HSP产生的免疫祖先系统可能在多大程度上涉及表达NK相关分子的CTL将具有重要意义。此外，对在脊椎动物进化中占有关键地位的两栖动物的NK/T细胞的明确描述将支持CD8 NK/T细胞代表着连接先天免疫系统和获得性免疫系统的重要进化步骤的假设。这一发现也证明了这种细胞类型在哺乳动物免疫中的重要性。最后，更好地了解非洲爪哇的细胞介导的细胞毒性可能对理解针对病毒病原体的免疫防御系统中的假定缺陷具有关键意义，这些病毒病原体正导致世界各地的两栖动物数量下降。这个项目的总体目标是利用我们的非洲爪哇模式，从进化的角度评估CD8 NK/T细胞在体内和体外对肿瘤、病毒和次要组织相容抗原的先天和获得性免疫反应中的作用，并探索共表达CD8和NK标记的T细胞(CD8 NK/T细胞)是细胞免疫的系统发育早期介质的想法。自然杀伤细胞和细胞毒性T淋巴细胞是两种重要的免疫细胞，参与防御病毒感染和肿瘤。最近的研究表明，存在一种具有中间特性的新细胞类型。该研究计划的目标是用青蛙而不是老鼠作为模型系统，从进化的角度更好地了解这种新型免疫细胞在对抗癌症和病毒感染的免疫防御中的作用。

CD8 cytotoxic T-lymphocytes (CTL) recognize and kill targets that express antigenic peptides in the context of major histocompatibility complex (MHC) class I molecules. As such, CTL are crucially involved in the generation of adaptive immunity against viruses and tumors. Natural killer (NK) cells play an active role in innate immunity by detecting and killing virally-infected or tumor cells that have down-regulated their surface MHC class I molecules thereby escaping surveillance by the adaptive immune system. Growing evidence suggests that some immune responses are mediated by CTL expressing NK-associated molecules (CD8/NK T-cells). The biology and physiological significance of the complexity and heterogeneity of NK-associated molecules and their expression by different effectors (e.g. CTL) is unclear. Since it is now well established in several species, including frogs, that certain heat shock proteins (e.g. gp96 or hsp70) elicit both adaptive CD8 T-cell mediated responses against the antigenic peptides they chaperone, and innate immune responses, it will be of significance to explore, for the first time, the extent to which this putative ancestral system of hsp-generated immunity may involve CTL that express NK-associated molecules. In addition, an unequivocal characterization of NK/T-cells in an amphibian that occupies a pivotal position in the evolution of vertebrates would support the hypothesis that CD8 NK/T-cells represent an important evolutionary step that bridges the innate and adaptive immune systems. This finding would also attest of the importance of this cell type in immunity of mammals. Finally, a better knowledge of cell-mediated cytotoxicity in Xenopus may have crucial implication with respect to understanding putative defects in the immune defense systems used against those viral pathogens that are causing world-wide declines of amphibian populations. The overall goal of this project is to take advantage of our Xenopus model to assess, from an evolutionary perspective, the role of CD8 NK/T cells, both in vitro and in vivo, in innate and adaptive immune responses to tumor, viral, and minor histocompatibility antigens as well as to explore the idea that T-cells co-expressing CD8 and NK markers (CD8 NK/T-cells) are phylogenetically early mediators of cellular immunity. Natural killer and cytotoxic T-lymphocytes are two important types of immune cells involved in defense against virus infections and tumor. Recent studies suggest the existence of a novel cell type with intermediate characteristics. The goal of the research program is to use the frog Xenopus rather than mice as a model system to better understand the role of this new type of immune cell in immune defense against cancer and virus infections from an evolutionary perspective.